Testosterone undecanoate compositions

ABSTRACT

The present disclosure is drawn to pharmaceutical compositions and oral dosage forms containing testosterone undecanoate, as well as related methods of treatment. In one embodiment, the oral dosage form can include a therapeutically effective amount of testosterone undecanoate and a pharmaceutically acceptable carrier. The dosage form can be formulated such that, when measured using a USP Type II apparatus in 1000 mL of 8 wt % Triton X-100 in water at 37° C. and 100 rpm, the oral dosage form releases at least 20% more testosterone undecanoate after the first 120 minutes than an equivalent dose testosterone undecanoate containing oral dosage form without the pharmaceutically acceptable carrier.

FIELD OF THE INVENTION

The present invention relates to solid testosterone undecanoatecontaining pharmaceutical compositions and oral dosage forms as well asassociated methods of treatment. Accordingly, this invention involvesthe fields of chemistry, pharmaceutical sciences, medicine and otherhealth sciences.

BACKGROUND OF THE INVENTION

The need for testosterone supplementation, often caused by testosteronedeficiency, is a condition that can affect both men and women.Testosterone deficiency can be accompanied by a variety of symptomsincluding sexual dysfunction, reduced muscle mass and muscle strength,depressed mood, and osteoporosis. Male hypogonadism and female sexualdysfunction is characterized by a deficiency of endogenous testosteroneproduction resulting in abnormally low levels of circulatingtestosterone. Currently, common testosterone therapy treatment caninclude administration of invasive intramuscular products, topical gels,topical solution and patches, or multiple units of liquid oral dosagecapsules. There are challenges and drawbacks associated with each ofthese therapies. For example, use of topical gels or topical solutionscan result in accidental transfer of the active agent to others, such aschildren or partners.

Current standard therapies for males aim at restoring physiologicallyrelevant levels of testosterone in serum. It is generally recognizedthat in a normal adult man of age 17 to 54 yrs, the average serumtestosterone (T) a major androgenic hormone in males, is between about300 ng/dL to about 1100 ng/dL, known as the eugonadal range.Testosterone replacement in males should in theory approximate thenatural, endogenous production of the hormone. The average male produces4-7 mg of testosterone per day in a circadian pattern, with maximalplasma levels attained in early morning and minimal levels in theevening.

Low or reduced sexual desire is a condition that impacts millions ofwomen, particularly those over the age of 50. Testosterone (T) levelscan steeply decline in women as they age or after surgical menopause.Endogenous testosterone levels in women at age 40 are one half of thoseof women at age 21 and endogenous testosterone levels in women afteroophorectomy are 50% less than before oophorectomy. There is strongindication that supplemental testosterone therapy may be beneficial forthe treatment of women with reduced sexual desire. Currently in theUnited States, there is no approved testosterone product available forthe treatment of female sexual dysfunction and reduced sexual desire.The human female has substantially lower normal blood levels of totaltestosterone (10-100 ng/dL compared to males ˜300-1100 ng/dL) so it canbe logically surmised that efficacious doses for women can besubstantially lower (about 10-50 times) than that for men.

While oral is typically the most preferred and patient friendly routefor administration, the oral delivery of testosterone as testosteroneremains a huge challenge. This is due to extremely poor bioavailabilityrequiring very high dose as well as the short serum half-life requiringfrequent dosing. These problems with orally administered testosteroneare primarily due to first pass metabolism. Moreover, direct, oraldelivery of testosterone is also known to cause enzyme inductionresulting in potential drug-drug interactions. Currently, modifiedtestosterones, in form of methyl analogue of testosterone, and as anundecanoate ester, testosterone undecanoate (TU) are available for oraladministration for patients in need of testosterone therapy. However,liver damage including cholestasis, peliosis hepatitis, nodularregenerative hyperplasia, and primary hepatic tumors has been reportedwith use of methyl testosterone. Testosterone undecanoate, a prodrug oftestosterone, containing oral dosage forms are marketed in variouscountries under various trade names, e.g. Andriol®, Restandol®, AndriolTestocap® etc., each of which are liquid filled soft-gelatin capsuleformulations containing about 40 mg of TU in a liquid carrier.Testosterone undecanoate is converted in vivo to pharmacologicallyactive testosterone.

However, a huge drawback of the current state of the art oral liquidtestosterone undecanoate formulations is that it has to be encapsulatedin a capsule dosage form presenting it with limitations with respect toacceptable capsule sizes and related drug loading limitations due totestosterone undecanoate's poor solubility. Such limitations presentchallenges with respect to patient compliance, because patientstypically have to take multiple capsule units in order to get asufficient dose to provide the desired efficacy. Additionally, liquidcapsule formulations tend to require more complicated and costlymanufacturing processes and often require special storage and handling.Moreover, liquid lipidic compositions can present oxidative instabilitychallenges with respect to testosterone and its derivatives. Due totestosterone undecanoate's poor solubility, the production of a solidoral dosage forms such as tablets, caplets, and particulates remains anarea of continuous research and development.

SUMMARY OF THE INVENTION

The present disclosure is drawn to pharmaceutical compositions and oraldosage forms containing testosterone undecanoate, as well as relatedmethods of treatment. In one embodiment, a solid composition isprovided. The dosage form can include a therapeutically effective amountof testosterone undecanoate and a pharmaceutically acceptable carrier.The oral dosage form can be formulated to release at least 35 wt % ofthe dosage form's testosterone undecanoate in the first 120 minutes whenmeasured using a USP Type II apparatus in 1000 mL of 8 wt % Triton X-100in water at 37° C. and 100 rpm. In one embodiment, the testosteroneundecanoate can be present in the composition as a solid particulate. Inyet a further embodiment, the carrier can be free of lipid substance, orlipophilic surfactant or hydrophilic surfactants.

In another embodiment, a solid oral dosage form is provided. The oraldosage form can include a therapeutically effective amount oftestosterone undecanoate and a pharmaceutically acceptable carrier. Thedosage form can be formulated such that, when measured using a USP TypeII apparatus in 1000 mL of 8 wt % Triton X-100 in water at 37° C. and100 rpm, the oral dosage form releases at least 20% more testosteroneundecanoate after the first 120 minutes than a equivalent dosetestosterone undecanoate containing oral dosage form without thepharmaceutically acceptable carrier. In one embodiment, testosteroneundecanoate is not present in the solid composition in a solubilizedform. In another embodiment the oral dosage form can be formulated toinclude the testosterone undecanoate dose in the form of solidparticulates. In another embodiment the oral dosage form of thisinvention can include a composition comprising solid particulates thatcan be solid testosterone undecanoate and/or a solid pharmaceuticallyacceptable carrier.

In yet another embodiment, a method for treating a subject in need oftestosterone therapy is provided. The method includes administering asolid oral dosage form of the present invention. In one embodiment, theadministration can be once daily. In another embodiment, theadministration can be once every twelve hours.

DETAILED DESCRIPTION

Before the present testosterone undecanoate compositions, oral dosageforms and related methods of use are disclosed and described, it is tobe understood that this invention is not limited to the particularprocess steps and materials disclosed herein, but is extended toequivalents thereof, as would be recognized by those ordinarily skilledin the relevant arts. It should also be understood that terminologyemployed herein is used for the purpose of describing particularembodiments only and is not intended to be limiting.

It should be noted that, the singular forms “a,” “an,” and, “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to “an excipient” includes reference to oneor more of such excipients, and reference to “the carrier” includesreference to one or more of such carriers.

DEFINITIONS

As used herein, the term “treatment,” when used in conjunction with theadministration of pharmaceutical compositions and oral dosage formcontaining testosterone undecanoate, refers to the administration of theoral dosage form and pharmaceutically acceptable composition to subjectswho are either asymptomatic or symptomatic. In other words, “treatment”can both be to reduce or eliminate symptoms associated with a conditionor it can be prophylactic treatment, i.e. to prevent the occurrence ofthe symptoms. Such prophylactic treatment can also be referred to asprevention of the condition.

As used herein, the terms “formulation” and “composition” are usedinterchangeably and refer to a mixture of two or more compounds,elements, or molecules. In some aspects the terms “formulation” and“composition” may be used to refer to a mixture of one or more activeagents with a carrier or other excipients. Furthermore, the term “dosageform” can include one or more formulation(s) or composition(s) providedin a format for administration to a subject. When any of the above termsis modified by the term “oral” such terms refer to compositions,formulations, or dosage forms formulated and intended for oraladministration to subjects.

As used herein, the term “lipophilic” when used in combination with bothsolid and liquid lipophilic additives, refers to additives that havepoor or no solubility in water. “Lipophilic surfactants” refer tolipophilic additives that have HLB values of 10 or less, preferablybetween 2 to 10. Conversely, the term “hydrophilic,” when used incombination with both solid and liquid hydrophilic additives, refers toadditives that have average or good solubility in water. “Hydrophilicsurfactants” are hydrophilic additives that have significant surfaceactive property and that have HLB values of more than 10.

As used herein, the term “lipid” or lipid substance” as used inconnection, with various compounds, refers to fatty acid (unlessotherwise specified, having chain length greater than C₆) or fatty acidesters or glycerides of fatty acid esters, mixtures thereof andderivatives thereof, although not including salts thereof.

As used herein, “subject” refers to a mammal that may benefit from theadministration of a drug composition or method of this invention.Examples of subjects include humans, and may also include other animalssuch as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals.In one embodiment, the subject is a human subject. In one embodiment,the human subject is a male. In another embodiment, the human subject isa female.

As used herein, the term “solid particulate” means relating to, orformed of minute separate particles, as of a granular substance orpowder and that is a solid at room temperature. The term“multiparticulate” represents coated or uncoated drug delivery system,in which the dosage of the drug is divided among several discretedelivery entities, in contrast to a single-unit delivery entity.Multiparticulate systems can be powder, granule, mini-tablets, beads,prills, pellets, or combinations thereof. The term “matrix” representscoated or uncoated drug delivery system, in which the dosage of the drugis a single-unit monolithic delivery entity, such as tablet.

The term “oral administration” represents any method of administrationin which an active agent can be administered by swallowing, chewing, orsucking of the dosage form; or admixing the dosage form or its contentswith food and/or beverage immediately prior to consuming.

As used herein, the terms “release”, “release rate”, are usedinterchangeably to refer to the discharge or liberation of a substance,including without limitation a drug, from the dosage form into asurrounding environment such as an aqueous medium either in vitro or invivo.

As used herein, an “effective amount” or a “therapeutically effectiveamount” of a drug refers to a non-toxic, but sufficient amount of thedrug, to achieve therapeutic results in treating a condition for whichthe drug is known to be effective. It is understood that variousbiological factors may affect the ability of a substance to perform itsintended task. Therefore, an “effective amount” or a “therapeuticallyeffective amount” may be dependent in some instances on such biologicalfactors. Further, while the achievement of therapeutic effects may bemeasured by a physician or other qualified medical personnel usingevaluations known in the art, it is recognized that individual variationand response to treatments may make the achievement of therapeuticeffects a somewhat subjective decision. The determination of aneffective amount is well within the ordinary skill in the art ofpharmaceutical sciences and medicine. See, for example, Meiner andTonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographsin Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein byreference.

As used herein, the term “C_(avg) or “C-average” is usedinterchangeably, and is determined as the AUC_(0-t) or the mean AUCdivided by the time period (t). For example, C_(avg-8h) is the averageplasma concentration over a period of 8 hours post-dosing determined bydividing the AUC₀₋₈ value by 8. Similarly, C_(avg-12h) is the averageplasma concentration over a period of 12 hours post-dosing determined bydividing the AUC₀₋₁₂ value by 12; C_(avg-24h) is the average plasmaconcentration over a period of 24 hours post-dosing determined bydividing the AUC_(0-24h) value by 24, and so on.

For the purpose of this invention, the average baseline plasmatestosterone concentration (T-C_(avg-B)) of the human subject refers tothe arithmetic mean of the total plasma testosterone concentrationsdetermined on at least two consecutive times prior to any androgentreatment. In one aspect, the plasma testosterone concentration of thehuman male can be determined by automated or manual immunoassay methods,liquid chromatography or liquid chromatography-tandem mass spectrometry(LC-MSMS) methods or equivalent methods or combination of methodsthereof.

As used herein, the terms “plasma testosterone concentration”, “serumtestosterone concentration” or “testosterone concentration in blood” areused interchangeably and refers to the total testosterone including bothfree and bound testosterone, present in the plasma, serum or blood of asubject.

The terms “carrier” or “pharmaceutically acceptable carrier” are usedinterchangeably and refer to a pharmaceutically acceptable substancesthat enable a solid dosage form and that alter the release rate and/orextent of the active agent, for example testosterone undecanoate, fromthe composition and/or the dosage form. In one aspect of the invention,a pharmaceutically acceptable carrier is a compound or a mixture ofcompounds that enables the release of testosterone undecanoate from anoral dosage composition, when tested using a USP Type II apparatus in1000 mL of 8 wt % Triton X-100 in water at 37° C. and 100 rpm, such thatthe oral dosage form releases at least 20% more testosterone undecanoateafter the first 120 minutes compared to an equivalent dose testosteroneundecanoate oral dosage form without the pharmaceutically acceptablecarrier.

As used herein, the term “delayed release” is defined as release oftestosterone undecanoate from the composition or oral dosage form which,upon contact with an aqueous medium, occurs in a time delayed mannerattributed either to the characteristics of the dosage form via forexample, coating, encapsulating shell, etc., or due to the inherentnature of the composition. When the oral dosage form or compositionincludes a conventional capsule shell, the delay in release iscalculated after the capsule shell is dissolved or compromised.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint. As used herein, aplurality of items, structural elements, compositional elements, and/ormaterials may be presented in a common list for convenience. However,these lists should be construed as though each member of the list isindividually identified as a separate and unique member. Thus, noindividual member of such list should be construed as a de factoequivalent of any other member of the same list solely based on theirpresentation in a common group without indications to the contrary.

As used herein, a pharmaceutical “formulation” or “composition” isdefined as including a pharmaceutically active agent and apharmaceutically acceptable carrier that may or may not be processed orincorporated into a dosage form.

As used herein, a plurality of items, structural elements, compositionalelements, and/or materials may be presented in a common list forconvenience. However, these lists should be construed as though eachmember of the list is individually identified as a separate and uniquemember. Thus, no individual member of such list should be construed as ade facto equivalent of any other member of the same list solely based ontheir presentation in a common group without indications to thecontrary.

Concentrations, amounts, levels and other numerical data may beexpressed or presented herein in a range format. It is to be understoodthat such a range format is used merely for convenience and brevity andthus should be interpreted flexibly to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges or decimalunits encompassed within that range as if each numerical value andsub-range is explicitly recited. As an illustration, a numerical rangeof “about 1 to about 5” should be interpreted to include not only theexplicitly recited values of about 1 to about 5, but also includeindividual values and sub-ranges within the indicated range. Thus,included in this numerical range are individual values such as 2, 3, and4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as wellas 1, 2, 3, 4, and 5, individually. This same principle applies toranges reciting only one numerical value as a minimum or a maximum.Furthermore, such an interpretation should apply regardless of thebreadth of the range or the characteristics being described.

Invention

Reference will now be made in detail to preferred embodiments of theinvention. While the invention will be described in conjunction with thepreferred embodiments, it will be understood that it is not intended tolimit the invention to those preferred embodiments. To the contrary, itis intended to cover alternatives, variants, modifications, andequivalents as may be included within the spirit and scope of theinvention as defined by the appended claims.

The present disclosure is drawn to pharmaceutical compositions and oraldosage forms containing testosterone undecanoate, as well as relatedmethods of treatment. In particular, it has been discovered thattestosterone undecanoate can be formulated into solid compositionscontaining solid testosterone undecanoate that are capable of providingthe necessary release, in vitro or in vivo, and bioavailability toprovide therapeutic effectiveness. For example, in one embodiment, asolid oral dosage form is provided. The solid oral dosage form caninclude a therapeutically effective amount of testosterone undecanoateand a pharmaceutically acceptable carrier. The solid oral dosage formcan include a solid composition comprising a therapeutically effectiveamount of testosterone undecanoate and a pharmaceutically acceptablecarrier. The solid composition of the present invention can beformulated to release at least 35 wt % of its testosterone undecanoatein the first 120 minutes, when measured using a USP Type II apparatus in1000 mL of 8 wt % Triton X-100 in water at 37° C. and 100 rpm.Similarly, the oral dosage form can be formulated to release at least 35wt % of the dosage form's testosterone undecanoate in the first 120minutes when measured using a USP Type II apparatus in 1000 mL of 8 wt %Triton X-100 in water at 37° C. and 100 rpm.

In another embodiment, a solid oral dosage form is provided. The oraldosage form can include a therapeutically effective amount oftestosterone undecanoate and a pharmaceutically acceptable carrier. Thedosage form can be formulated such that, when measured using a USP TypeII apparatus in 1000 mL of 8 wt % Triton X-100 in water at 37° C. and100 rpm, the oral dosage form releases at least 20% more testosteroneundecanoate after the first 120 minutes than a equivalent dosetestosterone undecanoate containing oral dosage form without thepharmaceutically acceptable carrier. The oral dosage forms and relatedsolid compositions disclosed herein do not form oil-in-water emulsionswhen contacted with water with adequate mixing within 15 minutes asobserved by appearance of uniform opaque or translucent liquid or byother appropriate means. The term “oil in water (0/W) emulsion,” as usedherein, refers to a multi-phase system wherein oil or oil-like smallglobules are dispersed in water. Such globules can have the averagediameters of greater than about 200 nm or exhibit absorbance of about0.5 or more when spectrophotometrically measured at about 400 nm. Theoil or oil-like globules can have the tendency to coalesce and aredistinctly different from thermodynamically stable micelles ormicroemulsions.

The oral dosage forms and related solid compositions disclosed herein donot include lipid substance. The oral dosage forms and related solidcompositions disclosed herein do not include lipid substance having afatty acid chain length greater than C₁₂.

In one embodiment, the oral dosage form of this invention can include asolid particulate which can be solid testosterone undecanoate and/or asolid pharmaceutically acceptable carrier. The solid oral dosage form ofthe present invention can be administered as any oral dosage form knownin the art. Specific examples of oral dosage forms include tablets,capsules, sachets, lozenges, granules, powders, fast melt, lyophilized,sprinkle, suspension or combinations thereof. In another embodiment, thedosage form is coated. In one embodiment, the solid composition can be amatrix. In one embodiment, the solid oral dosage form is a tablet or acapsule. In another embodiment oral dosage form is a multiparticulateoral dosage form. In another embodiment, the composition can bemultiparticulate. Regardless of the type, the oral dosage forms orcompositions can be formulated to provide modified, delayed, sustained,extended, and/or controlled release of the testosterone undecanoate. Themodified, delayed, extended, pulsatile, and/or controlled release can beachieved by any method known in the art so long as it does not interferewith the function of the solid oral dosage forms. Non-limiting examplesof such methods includes coatings, polymers, and the like. In oneembodiment, the oral dosage form can be uncoated. In one embodiment thesolid composition of the invention is a solid dispersion, solidsolution, molecular dispersion, co-precipitate, amorphate, solidifiedsuspension, admixture, eutectic mixture, melt extrude, drug-carriercomplex, thermosetting system, or combinations thereof.

The compositions of this invention can include compounds or systems thatincrease mean residence time of the composition/dosage form in thegastrointestinal tract to enable prolonged drug release resulting inlonger duration of action. This can be accomplished by using approachesthat delays stomach emptying, mucoadhesion, floatation, sedimentation,expansion, and/or modified shape systems.

The solid oral dosage forms the present invention can be manufactured astablet or capsule dosage forms either by dry granulation methods, or bywet granulation methods. For example, testosterone undecanoate can becombined with one or more pharmaceutically acceptable carrier andblended to get a homogenous mixture which can be compressed into atablet or disposed into a capsule. In another embodiment, the homogenousmixture can be kneaded with a binder solution to get a wet granulatemass which can be dried and sized, for example by passing through ASTMmesh #30. The resulting granules can be optionally blended withpharmaceutical aids such as diluents, lubricants, disintegrants etc, anddisposed into capsules or compressed into tablets. In another particularcase, the tablets can be coated. In one embodiment the tablet is amatrix tablet. In another embodiment, the tablet can be multi-layeredtablet dosage form which can achieve release characteristics that canaccommodate dose splitting.

The solid oral dosage forms can also be formulated using melt-extrusionprocesses alone or in combination with other known processes. Forexample, in one embodiment, an amount of testosterone undecanoate can behomogeneously combined with a sufficient amount of one or more carriersubstances prior to undergoing extrusion. The carrier suitable for thecompositions of this invention, specifically melt extrusion process, canbe lipophilic or hydrophilic carrier. Combinations of lipophilic andhydrophilic carriers may also be used.

For the purpose of current invention, the terms “melt” and “melting”should be interpreted broadly, and include not only the alteration froma solid state to a liquid state, but can also refer to a transition to aglassy state or a rubbery state in which it is possible for onecomponent of the mixture to get embedded more or less homogeneously intothe other. In particular cases, one component can melt and the othercomponent(s) can dissolve in the melt, thus forming a solution which,upon cooling, may form a solid composition having advantageousproperties. In another particular case, one component can melt and theother component(s) can suspend thus forming a suspension which uponcooling may form a solid suspension having advantageous properties.

The melt-extruded solid compositions used to make the solid oral dosageforms of the present disclosure can be granular, multiparticulates,pellets, beads, mini-tablets or tablets. The melt-extruded solids can beused alone as the solid oral dosage form or can be disposed intocapsules or formed into tablets.

The carrier for a melt-extruded composition and/or dosage form caninclude, but is not limited to, carriers such as ethyl cellulose,cellulose acetate phthalates, glyceryl distearate, acrylic acid andmethacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cyanoethyl methacrylate, aminoalkyl methacrylatecopolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acidalkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), methyl methacrylate, polymethacrylate, stearic acid,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer, poly(methacrylic acid anhydride), and glycidylmethacrylate copolymers.

In one embodiment, the carrier for a melt-extruded solid oral dosageform can be one or more pharmaceutically acceptable polymers including,but not limited to polyvinyl alcohol, polyvinyl pyrrolidone,polyethylene glycols having molecular weight of about 1000 to about20,000, gelatin, carbomer, poloxamer, hydroxypropyl methyl cellulose;hydroxypropyl ethyl cellulose hydroxypropyl cellulose, carboxymethylcellulose. It is noteworthy that some pharmaceutical carriers can beused in more than one manufacturing process, such as a wet milling ordry milling process as well as a melt extrusion process.

In a further aspect, the compositions of the current invention can beformulated to provide a gastro-retentive dosage form. In one embodiment,the gastro-retentive dosage form can be a capsule or a tablet. Inanother embodiment, the gastro-retentive dosage form can be retained inthe upper gastro intestinal tract for at least one hour post-dosing. Inanother embodiment, the gastro-retentive dosage form can be retained inthe upper gastro intestinal tract for at least two hours post-dosing. Inanother embodiment, the gastro-retentive dosage form can be retained inthe upper gastro intestinal tract for at least 4 hours post-dosing. Inanother embodiment, the gastro-retentive dosage form can be formulatedto float in the upper gastro intestinal tract after dosing. In anotherembodiment, the gastro-retentive dosage form is formulated to increasein the dosage form volume by at least 10% when it comes in contact withan aqueous use environment compared to its volume when it is not incontact with the aqueous use environment. In another embodiment, thegastro-retentive dosage form is formulated to adhere to the lining ofthe upper gastro intestinal tract wall after dosing.

The compositions and the oral dosage forms of the current invention canalso include one or more of the pharmaceutical process aids selectedfrom the group known in the art, consisting of binders, bufferants,diluents, disintegrants, flavors, colorants, taste-masking agents,resins, pH modifiers, lubricants, glidants, thickening agent, opacifyingagent, humectants, desiccants, effervescing agents, plasticizing agentsand the like.

In a further aspect, the dosage form can comprise two or more ofpopulations of testosterone undecanoate compositions of the presentinvention. In one embodiment, at least one of the populations can beformulated to start releasing testosterone undecanoate immediately intoa surrounding aqueous medium. In another embodiment, at least one of thepopulations can be formulated to start releasing testosteroneundecanoate after at least 2 hours. In another embodiment, at least onethe populations can be formulated to release testosterone undecanoateafter about 4 hours, or after about 6 hours, or after about 8 hours, orafter about 10 hours, into a surrounding aqueous medium.

In yet a further embodiment, at least one of the populations can beformulated to start releasing testosterone undecanoate immediately afteroral administration to a human. In one particular case, at least one ofthe populations can be formulated to start releasing testosteroneundecanoate in the duodenal region after oral administration to a human.In another particular case, at least one of the populations can beformulated to start releasing testosterone undecanoate in the smallintestine after oral administration to a human.

In yet a further embodiment, at least one of the populations includes apH sensitive substance. In a particular case, at least one of thepopulations can be formulated to start releasing testosteroneundecanoate at a pH of from about 1.0 to about 3.4. In anotherparticular case, at least one of the populations can be formulated tostart releasing testosterone undecanoate at a pH of from about 3.5 toabout 5.5. In another particular case, at least one of the populationscan be formulated to start releasing testosterone undecanoate at a pH offrom about 5.6 to about 6.8. In another particular case, at least one ofthe populations can be formulated to start releasing testosteroneundecanoate at a pH about 7.0 or more.

In yet another aspect, the dosage form comprising two or more ofpopulations of testosterone undecanoate compositions of the presentinvention is a capsule or a tablet or a granular admixture. In aparticular case, the dosage form is a capsule-in-capsule dosage form. Inanother particular case the dosage form is a tablet-in-capsule dosageform. In another particular case the dosage form is a tablet-in-tabletdosage form. In another particular case, the dosage form is a granulesand/or pellets in capsule dosage form. In another particular case, thedosage form is a granule, pellet and/or tablet in a capsule dosage form.

Non-limiting examples of the processes that can be used to prepare thecompositions and dosage forms of this invention include mixing melting,prilling, size reduction, melt-spray congealing, co-precipitation,co-crystallization, encapsulation, co-milling, spray or freeze drying,complexing, granulating, extruding, slugging, or combinations thereof.

The amount of testosterone undecanoate present in the oral dosage formsof the present invention can vary depending on the desired therapeuticeffect. For example, a solid oral dosage form intended to providetreatment of hypogonadism in males would likely have a greater amount oftestosterone undecanoate present in the oral dosage form than a similardosage form intended to treat sexual dysfunction in females. With thisin mind, in one embodiment, the oral dosage forms of the presentinvention can include testosterone undecanoate in an amount of about 0.5mg to about 750 mg. In another embodiment, the solid oral dosage form,wherein the testosterone undecanoate is present in an amount of about 1mg to about 500 mg. In another embodiment, the solid oral dosage form,wherein the testosterone undecanoate is present in an amount of about 5mg to about 400 mg. In another embodiment, the testosterone undecanoatecan be present in the oral dosage form in an amount of about 10 mg toabout 250 mg.

In one aspect the solid oral dosage form can be formulated foradministration to a human male and the testosterone undecanoate ispresent in an amount of about 50 mg to about 750 mg. In one embodiment,the solid oral dosage form is formulated for administration to a humanmale and the testosterone undecanoate is present in an amount of about75 mg to about 600 mg. In another embodiment, the solid oral dosage formis formulated for administration to a human male and the testosteroneundecanoate is present in an amount of about 100 mg to about 400 mg. Inyet another aspect, the solid oral dosage form is formulated foradministration to a human female and the testosterone undecanoate ispresent in an amount of about 0.5 mg to about 200 mg. In one embodiment,the solid oral dosage form is formulated for administration to a humanfemale and the testosterone undecanoate is present in an amount of about1 mg to about 100 mg. In another embodiment, the solid oral dosage formis formulated for administration to a human female and the testosteroneundecanoate is present in an amount of about 2 mg to about 50 mg.

The testosterone undecanoate can be present in the solid composition, ororal dosage form, in the crystalline or amorphous form or combinationsthereof. In another embodiment, the testosterone undecanoate can becontrolled precipitated, milled, micronized or nanosized, or combinationthereof. In another embodiment, the testosterone undecanoate can have amean particle diameter of about 50 μm or less. In another embodiment,the testosterone undecanoate can have a mean particle diameter of about40 μm or less. In another embodiment, the testosterone undecanoate canhave a mean particle diameter of about 30 μm or less. In anotherembodiment, the testosterone undecanoate can have a mean particlediameter of about 20 μm or less. In another embodiment, the testosteroneundecanoate can have a mean particle diameter of about 10 μm or less. Inanother embodiment, the testosterone undecanoate can have a meanparticle diameter of about 5 μm or less. In another embodiment, thetestosterone undecanoate can have a mean particle diameter of about 2 μmor less. In another embodiment, the testosterone undecanoate can have amean particle diameter of about 200 nm or less.

The testosterone undecanoate can be present in the solid oral dosageform as solid particulates. In one embodiment, the solid particulatesare not solubilized in the carrier present in oral dosage form. In oneembodiment, the solid particulates of testosterone undecanoate cancomprise 5% (w/w) or more of the testosterone undecanoate present in theoral dosage form. In one embodiment, the solid particulates oftestosterone undecanoate can comprise 15% (w/w) or more of thetestosterone undecanoate present in the oral dosage form. In anotherembodiment, the solid particulates of testosterone undecanoate cancomprise 30% (w/w) or more of the testosterone undecanoate present inthe oral dosage form. In another embodiment, the solid particulates oftestosterone undecanoate can comprise 50% (w/w) or more of thetestosterone undecanoate present in the oral dosage form. In anotherembodiment, the solid particulates of testosterone undecanoate cancomprise 70% (w/w) or more of the testosterone undecanoate present inthe oral dosage form. In another embodiment, the solid particulates oftestosterone undecanoate can comprise 90% (w/w) or more of thetestosterone undecanoate present in the oral dosage form.

In one embodiment, the testosterone undecanoate can be present in or onparticles having effective average particle sizes of less than 2000 nmor less in diameter. The particles can have at least one surfacestabilizer that can be adsorbed on or associated with the surface of theparticles having the testosterone undecanoate, or polymorph thereof.Preferably, the surface stabilizer adheres onto, or associates with, thesurface of the particles, but does not react chemically with theparticles or with other surface stabilizer molecules. Individuallyadsorbed molecules of the surface stabilizer are essentially free ofintermolecular cross-linkages. The relative amounts of the testosteroneundecanoate, or polymorph thereof, and surface stabilizer present in thecomposition of the present invention can vary widely. The amount of theindividual components can depend upon, among other things, theparticular polymorph selected, the hydrophilic-lipophilic balance (HLB),the melting point, and the surface tension of water solutions of thestabilizer. The concentration of the testosterone undecanoate, orpolymorph thereof, can vary from about 99.5% to about 0.001%, from about95% to about 0.1%, or from about 90% to about 0.5%, by weight, based onthe total combined weight of the testosterone undecanoate, or polymorphthereof, and the surface stabilizer(s), not including other excipients.Likewise, the concentration of the surface stabilizer(s) can vary fromabout 0.5% to about 99.999%, from about 5.0% to about 99.9%, or fromabout 10% to about 99.5%, by weight, based on the total combined dryweight of the testosterone undecanoate, or polymorph thereof, andsurface stabilizer(s), not including other excipients.

It has been discovered that solid oral dosage forms can be formulated toprovide the required drug release and bioavailability when appropriatecarrier is selected. The amount of the pharmaceutically acceptablecarrier used in the oral dosage form can vary depending on factors suchas the amount of testosterone undecanoate present in the oral dosageform. In one embodiment, the solid oral dosage form can have an amountof testosterone undecanoate to amount of pharmaceutically acceptablecarrier ratio of about 8:1 (w/w) to about 1:8 (w/w). In anotherembodiment, the solid oral dosage form can have an amount oftestosterone undecanoate to amount of pharmaceutically acceptablecarrier ratio of about 4:1 (w/w) to about 1:4 (w/w). In anotherembodiment, the solid oral dosage form can have an amount oftestosterone undecanoate to amount of pharmaceutically acceptablecarrier ratio of about 2:1 (w/w) to about 1:2 (w/w).

The pharmaceutically acceptable carriers that are included in the oraldosage forms of the present invention can act to facilitate thebioavailability of the testosterone undecanoate. In one embodiment, thepharmaceutically acceptable carrier can include hydrophilic additives,lipophilic additives, or combinations thereof. In one embodiment, thehydrophilic additive is not a hydrophilic surfactant. In anotherembodiment, the lipophilic additive is not a lipophilic surfactant. Inanother embodiment, the composition is free of triglyceride, animal andvegetable oils.

In another embodiment, the carrier can be free of hydrophilicsurfactants. In another embodiment, the formulation can include ahydrophilic surfactant that does not or does not substantiallycontribute to the solubility of the testosterone undecanoate within thecomposition. It is noteworthy, that the phrase “substantiallycontribute” as it refers to the hydrophilic surfactant's effect on thetestosterone undecanoate's solubility refers to the hydrophilicsurfactant solubilizing less than 10 wt % of the testosteroneundecanoate. In one embodiment, substantially contributes refers to thehydrophilic surfactant solubilizing less than 5 wt % of the testosteroneundecanoate. In one embodiment, substantially contributes refers to thehydrophilic surfactant solubilizing less than 1 wt % of the testosteroneundecanoate. In other embodiment the hydrophilic surfactant does notsolubilize testosterone undecanoate. In another embodiment the carrieris not a hydrophilic surfactant.

The oral dosage forms may also be free of oils. As used herein, the term“oils” refers to pharmaceutically acceptable glycerides that have atriglyceride content of at least 40 wt %. Similarly, another embodimentof the invention provides for the oral dosage form to be free oftriglycerides. In one embodiment, the pharmaceutically acceptablecarrier in the dosage form is not a lipid substance.

Non-limiting examples of pharmaceutically acceptable carriers caninclude methyl cellulose; ethyl cellulose; noncrystalline cellulose;microcrystalline cellulose; hypromellose (hydroxypropyl methylcellulose,for example, Methocel, having a viscosity range from 2 to about 140000cPs); hydroxyethyl cellulose; hydroxypropyl cellulose;carboxymethylcellulose or its salts or combinations thereof; dextrose;cellulose acetate; cellulose acetate pthalate; cellulose acetatebutyrate; cellulose acetate trimellitate; cellulose nitrate; carbomers;croscarmellose; cyclodextrins; β-cyclodextrins; α-cyclodextrin;dextrates; sorbitol; lactose; sucrose; maltose; galactose;polyvinylpyrrolidone (povidone K 12 to K120); crospovidone; polyvinylalcohol; glycerol; glucose; polyols; such as mannitol; xylitol orsorbitol or their combinations; polyethylene glycol esters; alginates;sodium alginate; poly(lactide coglycolide); gelatin; crosslinkedgelatin; agar-agar; sodium dodecyl sulfate; polyethylene glycols of molwt range from about 100 to about 20,000 or their mixtures; guar gum;xanthan gum; starches; gum arabic; dextrins; dibasic calcium phosphate;sodium starch glyco late; croscarmellose sodium; galactomannan;tricalcium phosphate; maltodextrin or its derivatives and theircombinations; polyoxyethylene stearate; carnuaba wax; poloxamers;deoxycholic acid; polyoxyl sorbitan derivatives; polysorbate; lauroylmacrogolglycerides; polyoxylglycerides; fatty alcohols; sugar esters;sugar ethers; shellacs; tocopherol; tocopherol polyethyleneglycolsuccinate; tocopherol succinate; tocopherol acetate; pentaerythritol;urea; stearic acid; stearic acid salts; hydroxystearic acid urethane;hydroxyalkyl xanthines; carrageenan; chitosan; benzyl alcohol; ethylalcohol; cetyl alcohol; cetosterayl alcohol; polycaprolactone;polylactic acid; polyglycolic acid; polylactide-co-glycolides; talc;magnesium stearate; fumed silica; micronized silica; hydrogenatedvegetable oils; capric acid; caprylic acid; undecanoic acid; oleic acid;linoleic acid; eicosapentaenoic acid; docosahexanoic acid;caprylic/capric mono and/or diglycerides; caprylic/capric triglyceride;caprylic/capric/lauric triglyceride; caprylocaproyl macrogolglycerides;oleoyl macrogolglycerides; corn glycerides; corn oil monoglycerides;mono-diglycerides of corn oil, coconut oil, safflower oil, sunfloweroil, maize oil; or mixtures thereof; glyceryl mono linoleate; glycerylstearate; glyceryl palmitostearate; glyceryl oleate; hydrogenated castoroils; medium and/or long chain mono-, di- or triglycerides; sodiumbenzoate; sodium acetate; acetylated monoglycerides; long-chain alcoholsand silicone derivatives; gallic acid; propyl gallate; ascorbic acid;ascorbyl palmitate; bentonite; vinyl pyrrolidone copolymers;hydrochloric acid; phosphoric acid; sulfuric acid; nitric acid; aceticacid; citric acid; tartaric acid; succinic acid; boric acid; phosphoricacid; acrylic acid; adipic acid; alginic acid, alkanesulfonic acid,amino acids, benzoic acid, butyric acid, carbonic acid, fatty acids,formic acid, fumaric acid, gluconic acid, isoascorbic acid, lactic acid,maleic acid, methanesulfonic acid, oxalic acid, propionic acid,salicylic acid, tannic acid, thioglycolic acid, toluenesulfonic acid;uric acid; amino acid ester; ammonium hydroxide, potassium hydroxide,sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide,magnesium hydroxide; magnesium aluminum hydroxide; magnesium aluminumsilicate, synthetic aluminum silicate, synthetic hydrotalcite,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, or a salt of aethylenediaminetetraacetic acid and its salts; titanium dioxide, fooddyes, lakes, natural vegetable colorants, iron oxides, silicates,sulfates, aluminum hydroxidecitric acid, sodium chloride, potassiumchloride, calcium sulfate, magnesium oxide, essential oils and ethylvanillin; styrene/divinyl benzene copolymers, quaternary ammoniumcompounds, triethyl citrate, acetyl triethyl citrate, acetyltributylcitrate, propylene glycol, phthalate esters (e.g., diethyl phthalate,dibutyl phthalate), castor oil, sorbitol and dibutyl seccateascorbicacid, sorbic acid, parabens, phenols, butylated hydroxyanisole,butylated hydroxytoluene, proteins (e.g., collagen, Zein, gluten, musselprotein, lipoprotein), glycerol fatty acid esters; acetylated glycerolfatty acid esters; lower alcohol fatty acids esters; polyethylene glycolfatty acids esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides lactic acid esters of mono/diglycerides;propylene glycol diglycerides; polyoxyethylene alkylethers;polyoxyethylene-polyoxypropylene block copolymers such as poloxamer—108,188, 217, 238, 288, 338, 407, 124, 182, 183, 212, 331, or 335, orcombinations thereof; trans-esterified vegetable oils; sterols;cholesterol; sterol derivatives; sucroglycerides; polyoxyethylenevegetable oils; and polyoxyethylene hydrogenated vegetable oils,lecithins, phospholipids, sodium docusate; dioctyl sulfosuccinate; acyllactylates; mono- and diacetylated tartaric acid esters of mono- anddiglycerides; succinylated monoglycerides, paraffin oil, paraffin wax,silicone oil, dimethicone, simethicone, silicon dioxide, macrogol 15hydroxystearate (Solutol), sucrose acetate isobutyrate, polyethoxylatedcholesterol; stearoyl polyoxyglycerides; acrylic acid polymers such asmethacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cyanoethyl methacrylate, aminoalkyl methacrylatecopolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acidalkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), methyl methacrylate, polymethacrylate, polyacrylamide,glycidyl methacrylate copolymers, and combinations thereof.

In one embodiment, the pharmaceutically acceptable carrier can includeat least one of polyvinyl alcohol, polyvinyl pyrrolidones, polyethyleneglycols having molecular weight from about 100 to about 20,000;propylene glycol; starches; sodium starch glycolate; croscarmellose;sucrose; lactose; cyclodextrins; carboxymethyl cellulose;microcrystalline cellulose, hydroxyl propyl methyl cellulose; ethylcellulose; carbomers; gelatin; poloxamers; sodium dodecyl sulfate;sodium docusate; sorbitan esters, polyoxyethylene sorbitan esters;glycerin; paraffin oil; silicone oils; magnesium aluminosilicates;silicon dioxide; ethyl alcohol; benzyl alcohol; benzyl benzoate;ascorbic acid; oleic acid; linoleic acid; stearic acid; capric acid;caprylic acid; caprylic/capric fatty acid mono and/or diglycerides;hydrogenated castor oil; corn oil macrogolglycerides; linoleic/oleicfatty acid mono- and/or diglycerides; caprylocaproyl macrogolglycerides;mono- and/or diglycerides of coconut oil or maize oil or safflower oilor sunflower oil or mixtures thereof; glycerol esters of saturatedC₁₂-C₁₈ fatty acid; glyceryl monostearate; glyceryl distearate; glycerylpalmitostearate; glyceryl behenate; glyceryl monolinoleate;triglycerides; oils; fatty acids; triethyl citrate; linoleoylmacrogolglycerides, lauroyl macrogolglycerides; sugar esters; acetylatedmono- and/or diglycerides; stearoyl polyoxyglycerides; trans-esterifiedvegetable oils; lecithin; phospholipids; polyethoxylated cholesterol;glyceryl oleate, cholesterol; tocopherol; tocopherol succinate; mediumand/or long chain mono-, diglycerides; polyoxyl castor oils or mixturesthereof.

In another embodiment, the pharmaceutically acceptable carrier caninclude at least one of polyvinyl alcohol, polyvinyl pyrrolidones,polyethylene glycols having molecular weight from about 100 to about20,000; cyclodextrins; maltodextrin; hydroxylpropyl methyl cellulose;carbomers; gelatin; poloxamers; sodium dodecyl sulfate; sodium docusate;sorbitan esters, polyoxyethylene sorbitan esters; ethyl alcohol; benzylalcohol; benzyl benzoate; oleic acid; linoleic acid; stearic acid;capric acid; caprylic acid; caprylocaproyl macrogolglycerides; corn oilmacrogolglycerides; glyceryl monostearate; glyceryl distearate; glycerylpalmitostearate; glyceryl monolinoleate; cholesterol; tocopherol;polyoxyl vegetable oils; triethyl citrate; linoleoyl macrogolglycerides,lauroyl macrogolglycerides; sugar esters; stearoyl polyoxyglycerides;lecithin; phospholipids; polyethoxylated cholesterol; or mixturesthereof.

In another embodiment, the pharmaceutically acceptable carrier caninclude at least one of polyvinyl alcohol, polyvinyl pyrrolidones,polyethylene glycols having molecular weight from about 100 to about20,000; cyclodextrins; maltodextrin; hydroxylpropyl methyl cellulose;carbomers; gelatin; poloxamers; sodium dodecyl sulfate; sodium docusate;polyoxyethylene sorbitan esters; ethyl alcohol; benzyl alcohol; benzylbenzoate; caprylocaproyl macrogolglycerides; corn oilmacrogolglycerides; polyoxyl castor oils; polyoxyl vegetable oils;triethyl citrate; linoleoyl macrogolglycerides, lauroylmacrogolglycerides; sugar esters; stearoyl polyoxyglycerides; ormixtures thereof.

In another embodiment, the pharmaceutically acceptable carrier caninclude at least one of polyvinyl alcohol, polyvinyl pyrrolidones,polyethylene glycols having molecular weight from about 100 to about20,000; propylene glycol; starches; sodium starch glycolate;croscarmellose; sucrose; lactose; cyclodextrins; carboxymethylcellulose; microcrystalline cellulose; hydroxyl propyl methyl cellulose;ethyl cellulose; carbomers; gelatin; sorbitan esters; glycerin; paraffinoil; silicone oils; magnesium aluminosilicates; silicon dioxide; ethylalcohol; benzyl alcohol; benzyl benzoate; ascorbic acid; oleic acid;linoleic acid; stearic acid; capric acid; caprylic acid; caprylic/capricmono and/or diglycerides; hydrogenated castor oil; mono- and/ordiglycerides of coconut oil or, maize oil, safflower oil, sunflower oil,or mixtures thereof; glyceryl monostearate; glyceryl distearate;glyceryl palmitostearate; glyceryl behenate; glyceryl mono linoleate;glyceryl oleate, cholesterol; tocopherol; tocopherol succinate; mediumand/or long chain mono-, diglycerides; fatty acids; triethyl citrate;linoleoyl macrogolglycerides, lauroyl macrogolglycerides; sugar esters;acetylated mono- and/or diglycerides; steroyl polyoxyglycerides;trans-esterified vegetable oils; lecithin; phospholipids; or mixturesthereof.

In another embodiment, the pharmaceutically acceptable carrier caninclude at least one of polyvinyl alcohol, polyvinyl pyrrolidones,polyethylene glycols having molecular weight from about 100 to about20,000; propylene glycol; starches; sodium starch glycolate;croscarmellose; sucrose; lactose; cyclodextrins; carboxymethylcellulose; microcrystalline cellulose, hydroxyl propyl methyl cellulose;ethyl cellulose; carbomers; gelatin; poloxamers; sodium dodecyl sulfate;sodium docusate; polyoxyethylene sorbitan esters; glycerin; paraffinoil; silicone oils; magnesium aluminosilicates; silicon dioxide; ethylalcohol; benzyl alcohol; benzyl benzoate; ascorbic acid; oleic acid;linoleic acid; stearic acid; capric acid; caprylic acid; hydrogenatedcastor oil; caprylocaproyl macrogolglycerides; cholesterol; tocopherol;tocopherol succinate; polyoxyl castor oils; polyethoxylated cholesterolor mixtures thereof.

In another embodiment, the preferred pharmaceutically acceptable carrieris free of lipophilic additives and can include at least one ofpolyvinyl alcohol, polyvinyl pyrrolidones, polyethylene glycols havingmolecular weight from about 100 to about 20,000; cyclodextrins;maltodextrin; hydroxylpropyl methyl cellulose; carbomers; gelatin;poloxamers; sodium dodecyl sulfate; sodium docusate; polyoxyethylenesorbitan esters; ethyl alcohol; benzyl alcohol; benzyl benzoate;caprylocaproyl macrogolglycerides; polyoxyl castor oils; polyoxylvegetable oils; triethyl citrate; lauroyl macrogolglycerides; sugaresters; stearoyl polyoxyglycerides or mixtures thereof.

In yet another embodiment, the pharmaceutically acceptable carrier isfree of hydrophilic surfactants and includes at least one of polyvinylalcohol, polyvinyl pyrrolidones, polyethylene glycols having molecularweight from about 100 to about 20,000; propylene glycol; starches;sodium starch glycolate; croscarmellose; sucrose; lactose;cyclodextrins; carboxymethyl cellulose; microcrystalline cellulose,hydroxylpropyl methyl cellulose; ethyl cellulose; carbomers; gelatin;sorbitan esters, glycerin; paraffin oil; silicone oils; magnesiumaluminosilicates; silicon dioxide; ethyl alcohol; benzyl alcohol; benzylbenzoate; ascorbic acid; oleic acid; linoleic acid; stearic acid; capricacid; caprylic acid; caprylic/capric mono and/or diglycerides;hydrogenated castor oil; mono- and/or diglycerides of coconut oil or,maize oil, safflower oil, sunflower oil, or mixtures thereof; glycerylmonostearate; glyceryl distearate; glyceryl palmitostearate; glycerylbehenate; glyceryl monolinoleate; glyceryl oleate, cholesterol;tocopherol; tocopherol succinate; medium and/or long chain mono-,diglycerides; fatty acids; triethyl citrate; linoleoylmacrogolglyceride; lauroyl macrogolglycerides; sugar esters; acetylatedmono- and/or diglycerides; steroyl polyoxyglycerides; trans-esterfiedvegetable oils; lecithin; phospholipids; or mixtures thereof.

In another embodiment, the pharmaceutically acceptable carrier is freeof lipophilic surfactants and includes at least one of polyvinylalcohol, polyvinyl pyrrolidones, polyethylene glycols having molecularweight from about 100 to about 20,000; propylene glycol; starches;sodium starch glycolate; croscarmellose; sucrose; lactose;cyclodextrins; carboxymethyl cellulose; microcrystalline cellulose,hydroxylpropyl methyl cellulose; ethyl cellulose; carbomers; gelatin;poloxamers; sodium dodecyl sulfate; sodium docusate; polyoxyethylenesorbitan esters; glycerin; paraffin oil; silicone oils; magnesiumaluminosilicates; silicon dioxide; ethyl alcohol; benzyl alcohol; benzylbenzoate; ascorbic acid; oleic acid; linoleic acid; stearic acid; capricacid; caprylic acid; hydrogenated castor oil; caprylocaproylmacrogolglycerides; cholesterol; tocopherol; tocopherol succinate;polyoxyl castor oils; polyethoxylated cholesterol or mixtures thereof.

In another embodiment, the pharmaceutically acceptable carrier is freeof lipid substance and includes at least one of polyvinyl alcohol,polyvinyl pyrrolidones, polyethylene glycols having molecular weightfrom about 100 to about 20,000; cyclodextrins; maltodextrin;hydroxylpropyl methyl cellulose; carbomers; gelatin; poloxamers; ethylalcohol; benzyl alcohol; benzyl benzoate or combinations thereof.

In yet another embodiment, the pharmaceutically acceptable carrier caninclude polyvinyl alcohol, polyvinyl pyrrolidones, polyethylene glycolshaving molecular weight from about 1000 to about 20,000, or combinationthereof. In a further embodiment, the solid composition of the currentinvention includes less than 30 wt % of polyethylene glycol. In aparticular embodiment, the solid composition of the current inventionincludes from about 0.1 wt % to about 27 wt % of polyethylene glycol. Inanother embodiment, the solid composition of the current inventionincludes from about 3 wt % to about 20 wt % of polyethylene glycol. Inanother particular embodiment, the solid composition of the currentinvention can include from about 6 wt % to about 15 wt % of polyethyleneglycol.

In a further embodiment, the solid composition or dosage form of thecurrent invention includes about 45% or less of a lipid substance. In afurther embodiment, the solid composition or dosage form includes about30% or less of a lipid substance. In a further embodiment, the solidcomposition or dosage form includes about 15% or less of a lipidsubstance. In a further embodiment, the solid composition or dosage formincludes about 5% or less of a lipid substance. In another particularembodiment, the solid composition or dosage form is free of lipidsubstance. In another embodiment, the pharmaceutical carrier in thedosage form does not include a lipid substance with chain length greaterthan C₁₂.

The solid oral dosage forms are capable of providing adequate in vivobioavailability to provide therapeutic effect for testosterone therapyof both female and male subjects. In one aspect of the invention, theoral dosage form can be formulated to have a delayed release such thatthe testosterone undecanoate does not have any release, or anysignificant (not more than 10 wt %) release, in the first 15 minutesfollowing administration. It has been discovered that by delaying theinitial release of the testosterone undecanoate for this time period,the oral dosage form provides a pharmacokinetic profile that may be moreacceptable than when the testosterone undecanoate is allowed to releaseimmediately.

With this in mind, the solid oral dosage forms of the present inventioncan be formulated to release about 85 wt % or less of the testosteroneundecanoate in the first 30 minutes following administration to asubject. In one embodiment, the solid oral dosage form can release lessthan 70 wt % of the testosterone undecanoate in the first 30 minutesfollowing administration. In another embodiment, the solid oral dosageform can be formulated to release at least 35 wt % of the testosteroneundecanoate in the first 120 minutes following administration to a humansubject. In another embodiment, the solid oral dosage form can beformulated to release at least 45 wt % of the testosterone undecanoatein the first 120 minutes following administration to a human subject. Inyet a further embodiment, the solid oral dosage form can be formulatedto release at least about 50 wt % in the first 120 minutes followingadministration to a human subject.

As discussed above, the solid oral dosage forms of the present inventionprovide adequate bioavailability of the testosterone undecanoate so asto generate therapeutically effective pharmacokinetic levels oftestosterone undecanoate and testosterone, without the need toadminister excessive amounts of the active agent. In one embodiment, thedosage form when administered to a human male the oral dosage provides adose to plasma total testosterone C_(avg) ratio of 4.5×10⁴ dL to 4×10⁶dL. In another embodiment, the dosage form when administered to a humanmale the oral dosage provides a dose to plasma total testosteroneC_(avg) ratio of 6×10⁴ dL to 3×10⁶ dL. In another embodiment, the dosageform when administered to a human male, the oral dosage provides a doseto plasma testosterone C_(avg) ratio of 9×10⁴ dL to 2×10⁶ dL.

In one embodiment, the dosage form when administered to a human female,the oral dosage provides a dose to plasma total testosterone C_(avg)ratio of 5×10³ dL to 2×10⁷. In another embodiment, the dosage form whenadministered to a human female, the oral dosage provides a dose toplasma total testosterone C_(avg) ratio of 1×10⁴ dL to 1×10⁷ dL. Inanother embodiment, the dosage form when administered to a human female,the oral dosage provides a dose to plasma total testosterone C_(avg)ratio of 2×10⁴ dL to 5×10⁶ dL.

In one embodiment, the oral dosage form, when after administration to ahuman male, can provide a plasma total testosterone C_(avg) of about 300ng/dL to about 1100 ng/dL. In another embodiment, the oral dosage form,when after administrations to a human male, can provide a plasma totaltestosterone C_(avg) of about 350 ng/dL to about 800 ng/dL. In anotherembodiment, the oral dosage form, when after administrations to a humanmale, can provide a plasma total testosterone C_(avg) of about 400 ng/dLto about 600 ng/dL. In yet another embodiment, the oral dosage form,when after administrations to a human male, the oral dosage formprovides a plasma total testosterone undecanoate C_(avg) of about 1.5ng/mL to about 1 μg/mL. In another embodiment, the oral dosage form,when after administrations to a human male, can provide a plasma totaltestosterone undecanoate C_(avg) of about 10 ng/mL to about 850 ng/mL.

When administered to a human female, the oral dosage forms of thepresent invention can be formulated to provide a plasma totaltestosterone C_(avg) of about 1 ng/dL to about 100 ng/dL. In anotherembodiment, when administered to a human female, the oral dosage formcan provide a plasma total testosterone C_(avg) of about 20 ng/dL toabout 80 ng/dL. In yet a further embodiment, when administered to ahuman female, the oral dosage form can provide a plasma totaltestosterone C_(avg) of about 30 ng/dL to about 70 ng/dL.

In a further embodiment, the dosage forms can be formulated such thatwhen administered to a human subject, provides a ratio of serumtestosterone undecanoate C_(avg) to serum total testosterone C_(avg) ofabout 3:1 to about 100:1. In a further embodiment, the dosage forms canbe formulated such that when administered to a human subject, provides aratio of serum testosterone undecanoate C_(avg) to serum totaltestosterone C_(avg) of about 4:1 to about 50:1.

In one embodiment, a single dose of the testosterone undecanoatecomposition or oral dosage form can provide a C_(avg) for testosteroneof about 300 ng/dL or more from about 0.5 hours to about 24 hours afteroral administration with a meal. In a further embodiment, a single doseof a testosterone undecanoate composition or oral dosage form canprovide a C_(avg) for plasma total testosterone of about 300 ng/dL ormore at about 20 hours after oral administration with a meal. In yet afurther embodiment, a single dose of the testosterone undecanoatecomposition can provide a C_(avg) for plasma total testosterone of about300 ng/dL or more at about 18 hours after oral administration with ameal. In still a further embodiment, a single dose of the testosteroneundecanoate oral dosage form can provide a C_(avg) for plasma totaltestosterone of about 300 ng/dL or more at about 16 hours after oraladministration with a meal. In still a further embodiment, a single doseof the testosterone undecanoate oral dosage form can provide a C_(avg)for plasma total testosterone of about 300 ng/dL or more at about 12hours after administration after oral administration with a meal. Instill a further embodiment, a single dose of the testosteroneundecanoate oral dosage form can provide a C_(avg) for plasma totaltestosterone of about 300 ng/dL or more at about 8 hours after oraladministration with a meal. The meal that is administered with thecomposition or oral dosage form can be a standard meal (comprising about30 g to about 35 g fat).

In another embodiment, a pharmaceutical oral dosage form, whenadministered once daily, provides a plasma total testosterone C_(avg) ofabout 300 ng/dL to 700 ng/dL. In another embodiment, a pharmaceuticaloral dosage form, when administered once daily, provides a plasma totaltestosterone C_(avg) of about 300 ng/dL to 600 ng/dL.

In one embodiment, the pharmaceutical oral dosage form can, whenadministered twice daily (e.g. once every 12 hours), provide a plasmatotal testosterone C_(avg) of about 300 ng/dL to 1000 ng/dL. In anotherembodiment, the pharmaceutical oral dosage form can, when administeredtwice daily, provide a plasma total testosterone C_(avg) of about 350ng/dL to 800 ng/dL. In another embodiment, the pharmaceutical oraldosage form can, when administered twice daily, provide a plasma totaltestosterone C_(avg) of about 400 ng/dL to 600 ng/dL. In anotherembodiment, the pharmaceutical oral dosage form can, when administeredtwice daily, provide a plasma total testosterone C_(avg) of about 300ng/dL to 1000 ng/dL. In another embodiment, the pharmaceutical oralform, when administered twice daily such that more than 100 mgtestosterone undecanoate is administered during the day and less than100 mg administered during the night, can provide a plasma totaltestosterone C_(avg) of about 300 ng/dL to 1000 ng/dL. In anotherembodiment, the pharmaceutical oral form, when administered twice dailysuch that more than 100 mg testosterone undecanoate is administeredduring the day and less than 100 mg administered during the night, canprovide a plasma total testosterone C_(avg) of about 300 ng/dL to 800ng/dL. In another embodiment, the pharmaceutical oral form, whenadministered twice daily such that more than 100 mg testosteroneundecanoate is administered during the day and less than 100 mgadministered during the night, can provide a plasma total testosteroneC_(avg) of about 400 ng/dL to 700 ng/dL. In another embodiment, thepharmaceutical oral form, when administered twice daily such that morethan 100 mg testosterone undecanoate is administered during the day andless than 100 mg administered during the night, can provide a plasmatotal testosterone C_(avg) of 400 ng/dL to 600 ng/dL.

The oral dosage forms of the present invention can be used to treattestosterone deficiency in post menopausal women. In one embodiment, apharmaceutical oral dosage form is provided that, when administered oncedaily to post menopausal women, provides a plasma total testosteroneC_(avg) of about 10 ng/dL to 100 ng/dL. In another embodiment, apharmaceutical oral dosage form is provided that, when administered oncedaily to post menopausal women, provides a plasma total testosteroneC_(avg) of about 20 ng/dL to 60 ng/dL. In another embodiment, apharmaceutical oral dosage form is provided that, when administered oncedaily to post menopausal women, provides a plasma total testosteroneC_(avg) of about 20 ng/dL to 40 ng/dL

The oral dosage forms disclosed herein can also be used to treattestosterone deficiency in pre-menopausal women. In another embodiment,a pharmaceutical oral dosage form is provided that, when administeredonce daily to pre menopausal women in order to provides, plasma totaltestosterone C_(avg) of about 10 ng/dL to 100 ng/dL. In anotherembodiment, a pharmaceutical oral dosage form is provided that, whenadministered once daily to pre menopausal women in order to provides,plasma total testosterone C_(avg) of about 20 ng/dL to 60 ng/dL. Inanother embodiment, a pharmaceutical oral dosage form is provided that,when administered once daily to pre menopausal women in order toprovides, plasma total testosterone C_(avg) of about 20 ng/dL to 40ng/dL.

The oral dosage forms may also be used to treat testosterone deficiencyin perimenopausal women as well as in oopherectomized women. In oneembodiment, a pharmaceutical oral dosage form is provided that, whenadministered once daily to perimenopausal women, provides a plasma totaltestosterone C_(avg) of about 10 ng/dL to 100 ng/dL. In one embodiment,a pharmaceutical oral dosage form is provided that, when administeredonce daily to peri-menopausal women, provides a plasma totaltestosterone C_(avg) of about 20 ng/dL to 60 ng/dL. In one embodiment, apharmaceutical oral dosage form is provided that, when administered oncedaily to peri-menopausal women, provides a plasma total testosteroneC_(avg) of about 20 ng/dL to 40 ng/dL. In one embodiment, apharmaceutical oral dosage form is provided that, when administered oncedaily to oopherectomized women, provides a plasma total testosteroneC_(avg) of about 10 ng/dL to 100 ng/dL. In one embodiment, apharmaceutical oral dosage form is provided that, when administered oncedaily to oopherectomized women, provides a plasma total testosteroneC_(avg) of about 20 ng/dL to 60 ng/dL. In one embodiment, apharmaceutical oral dosage form is provided that, when administered oncedaily to oopherectomized women, provides a plasma total testosteroneC_(avg) of about 20 ng/dL to 40 ng/dL.

The oral dosage forms of the present invention can be used to treatsubjects in need of testosterone therapy, both males and females. Inanother embodiment, a method of treating a subject in need oftestosterone therapy is provided that includes administering to thesubject any of the solid oral dosage forms of the present invention.Depending on the particular oral dosage form and the needed therapy, theadministration can be done once every 24 hours, once every 12 hours, oronce every eight hours. In one embodiment, the administration caninclude more than one unit of the solid oral dosage form. In oneembodiment, the subject can be a human male and the solid oral dosageform provides a daily dose of testosterone undecanoate of about 50 mg toabout 1500 mg per day. In another embodiment, the subject can be a humanfemale and the solid oral dosage form can provide a daily dose oftestosterone undecanoate of 0.5 to 200 mg per day.

The testosterone undecanoate dosage compositions and oral dosage formsdisclosed herein can be orally administered in a 24 hours' dosingregimen (also referred to as or a daily dosing regimen) that is suitableto the needs of the subject. The 24 hours' dosing regimen can includeadministering the dosage forms after meals in the morning, at aboutnoon, in the evening, at about night time or combinations thereof. The24 hours' dosing regimen can include dosing one or more dosage units atone or more administration times.

The compositions and oral dosage forms disclosed herein can be orallyadministered with food without regards to the food or food content. Inone embodiment, the oral dosage form can be orally administered withoutfood. In another embodiment, the composition or oral dosage form can beadministered with a meal, such as a meal that provides about 200calories to about 1000 calories of energy. In another embodiment, thecomposition or oral dosage form can be administered with a meal thatprovides about 50% of the calories from the fat. In another embodiment,the composition or oral dosage form can be administered with a high-fat,high calorie meal. In another embodiment, the composition or oral dosageform can be administered with a standard meal that provides about 500calories to about 1000 calories of energy. The compositional make-up ofthe meals that are administered can vary depending on the tastes anddietary needs of a subject. However, in some situations it may bebeneficial to administer the compositions and oral dosage forms withmeals that provide no fat to about 50 g of fat. In one embodiment, themeal can provide about 10 g to about 50 g of fat. In yet a furtherembodiment, the meal can provide 15 g to about 35 g of fat. In oneembodiment, when the oral dosage form is administered to a human female,it can be done without regard to the presence of or nutritional make-upof a meal.

In another embodiment, when administering the oral dosage form, thetotal daily dose of the testosterone undecanotate administered to humansubject with standard meal is between about 20% to about 70% of thetotal daily dose administered without meals, for a similar therapeuticbenefit.

It has been surprisingly discovered that the testosterone undecanoateoral dosage forms of the present invention can provide in vitro releaseof less than about 85% of the testosterone undecanoate in the oraldosage form in the first 30 minutes, and that such release provides,upon a single oral administration with meals to a human subject, about10% or more testosterone undecanoate AUC as compared to an equivalentdose of testosterone undecanoate in an immediate release dosage capsuleadministered under same conditions. The in vitro release profile isdetermined in about 1000 mL of 8% w/v Triton X-100 solution at about 37°C. in an USP Type-2 Apparatus at about 100 rpm. Immediate release dosageforms are dosage forms that release more than 85% of the testosteroneundecanoate in the dosage form within the first 30 minutes in the abovein vitro release conditions.

In one embodiment, the testosterone undecanoate oral dosage forms of thecurrent invention, when compared to an equivalent dose testosteroneundecanoate containing immediate release dosage form, can provide upon asingle oral administration with meal to a human subject about 15% ormore testosterone undecanoate AUC. In another embodiment, thetestosterone undecanoate oral dosage form can provide 10% or moretestosterone undecanoate bioavailability as compared to an equivalentlydosed immediate release oral dosage form. In another embodiment, thetestosterone undecanoate oral dosage form can provide 10% or morereduction in the inter-subject variability of the testosteroneundecanoate C_(max), testosterone undecanoate AUC, or both as comparedto an equivalently dosed immediate release oral dosage form. In anotherembodiment, the testosterone undecanoate oral dosage form can provide10% or more testosterone exposure or bioavailability in subjects ascompared to equivalent dosed immediate release oral dosage forms. Inanother embodiment, the testosterone undecanoate oral dosage form canprovide 10% or more reduction in the variability of plasma totaltestosterone C_(max), testosterone AUC, or both.

The need for testosterone therapy can be associated with a variety ofconditions, and thus the oral dosage forms of the present invention canbe used to treat a variety of conditions. Generally, the compositionsand oral dosage forms of the present invention can be used to treat anycondition associated with testosterone deficiency, including completeabsence, of endogenous testosterone. In one embodiment, the subject canbe a male and the need for testosterone therapy can be associated with acondition selected from the group consisting of hygonadism; erectiledysfunction; Klienfelter Syndrome; reduced libido; low muscle mass, andlow bone density; metabolic syndrome, and combinations thereof.

In another embodiment, the subject can be a human female and the needfor testosterone therapy can be associated with a condition selectedfrom the group consisting of hypoactive sexual desire disorder, arousaldisorder, dyspareunia, anorgasmia, and combinations thereof. In furtherembodiments, the oral dosage form of the present disclosure can beadministered to menopausal women to can achieve one or more of thefollowing: increase their sexual desire, increase their sexual activity,increase their libido, increase their sexual fantasy, increasesatisfaction in their sexual activity, increase their subjective qualityof sexual acts, increase their frequency of sexual thoughts, increasetheir self reported mood, increase their self reported energy, increasetheir bone mineral density, increase their cognitive function, treattheir hormone-related depression, treat their arousal disorder, or treattheir hypoactive sexual disorder.

Other examples of conditions associated with testosterone deficiencythat can also be treated using the oral dosage capsules and/orcompositions of the present invention are also provided below. It isunderstood that some of the conditions are gender specific while othersmay be treated in both genders. Knowledge of such conditions is wellwithin the knowledge of own of ordinary skill in the art. With this inmind, additional conditions that can be treated with the compositionsand oral dosage forms of the present invention include, but are notlimited to congenital or acquired primary hypogonadism, hypogonadotropichypogonadism, cryptorchidism, bilateral torsion, orchitis, vanishingtestis syndrome, orchidectomy, Klinefelter's syndrome, post castration,eunuchoidism, hypopituitarism, endocrine impotence, infertility due tospermatogenic disorders, impotence, male sexual dysfunction (MSD)including conditions such as premature ejaculation; erectiledysfunction, decreased libido, and the like, micropenis andconstitutional delay, penile enlargement, appetite stimulation,testosterone deficiency associated with chemotherapy, testosteronedeficiency associated with toxic damage from alcohol, testosteronedeficiency associated with toxic damage from heavy metal, osteoporosisassociated with androgen deficiency, hot flashes, dry and thin skin,weight gain, and combinations thereof.

Other conditions that can be treated by the compositions and oral dosageforms disclosed herein include idiopathic gonadotropin, LHRH deficiency,or pituitary hypothalamic injury from tumors, trauma, or radiation.Typically, these subjects have low serum testosterone levels but havegonadotropins in the normal or low range. In one embodiment, thecompositions or oral dosage forms may be used to stimulate puberty incarefully selected males with clearly delayed puberty not secondary topathological disorder. In another embodiment, the compositions and oraldosage forms may be used in female-to-male transsexuals in order tomaintain or restore male physical and sexual characteristics includingbody muscle mass, muscle tone, bone density, body mass index (BMI),enhanced energy, motivation and endurance, restoring psychosexualactivity etc. In some embodiments, the testosterone undecanoatecompositions and oral dosage capsules may be useful in providinghormonal male contraception. Additionally, testosterone therapy can alsobe used to improve the quality of life of subjects suffering forconditions such as decreased libido, anemia due to marrow failure, renalfailure, chronic respiratory or cardiac failure, steroid-dependentautoimmune disease, muscle wasting associated with various diseases suchas AIDS, preventing attacks of hereditary angioedema or urticaria;andropause, and palliating terminal breast cancer. In some situations,certain biomarkers such as for example, increased SHBG levels, can beused to diagnose a subject who may be in need of testosterone therapy.These biomarkers can be associated with conditions/disease states suchas anorexia nervosa, hyperthyroidism, hypogonadism, androgeninsensitivity/deficiency, alcoholic hepatic cirrhosis, primary biliarycirrhosis, and the like.

Subjects that can be treated by the testosterone undecanoatecompositions and oral dosage capsule of the present disclosure can beany male or female in need thereof. In particular, in one embodiment,the human male may be at least 14 years of age. In another embodiment,the human male is an adult of at least age 30. In a further embodiment,the subject can be an adult male of at least age 50. In yet a furtherembodiment, the subject can be an adult male of at least age 60.

As discussed above, the compositions and oral dosage forms disclosedherein can be used to treat testosterone deficiency in human males. Inone embodiment, the human male being treated can have an averagebaseline plasma testosterone concentration (T-C_(avg-B)) of about 400ng/dL or less. In another embodiment, the human male being treated canhave an average baseline plasma testosterone concentration of about 350ng/dL or less. In another embodiment, the human male being treated canhave an average baseline plasma testosterone concentration of about 300ng/dL or less. In another embodiment, the human male being treated canhave an average baseline plasma testosterone concentration of about 250ng/dL or less. In still another embodiment, the human male being treatedcan have an average baseline plasma testosterone concentration of aboutof about 190 ng/dL or less. In still a further embodiment, the humanmale has an average baseline plasma testosterone concentration(T-C_(avg-B)) of about 400 ng/dL or less, along with a co-morbidcondition of insulin resistance.

Further, there are several biomarkers that can be used to identifypatients who need testosterone therapy. Accordingly, in one embodiment,the human male being treated can have a low density lipoproteins (LDL)level in greater than about 130 mg/dL of blood. In another embodiment,the human male being treated can have a high density lipoproteins (HDL)level less than about 40 mg/dL of blood. In still another embodiment,the human male being treated can have a total cholesterol level greaterthan about 220 mg/dL of blood. In yet a further embodiment, the humanmale being treated can have an average TG (triglycerides) levels greaterthan 250 mg/dL of blood. In one embodiment, the testosterone undecanoatedosage forms of the current invention can be administered to human malewhose bioavailable or free or un-bound plasma estradiol levels are about20 pg/mL or less. In another embodiment, dosage forms of the currentinvention can be administered to human male who has a ratio of thebioavailable or free or unbound plasma testosterone level to thebioavailable or free or un-bound plasma estradiol level at about 100 orless.

The testosterone undecanoate compositions and oral dosage forms of thecurrent invention can be administered orally to a human male who has anaverage body mass index (BMI) of about 30 kg/m² or more. In anotherembodiment, the human male has an average BMI of about 37 kg/m² or more.In a further embodiment, the subject male being treated can have a serumsex hormone binding globulin (SHBG) levels of about 40 nmol/L or more.In yet still another embodiment, the human male being treated can have aserum SHBG levels of about 60 nmol/L or more.

The compositions and associated oral dosage forms of the presentinvention can be used in conjunction with or as a component of adiagnostic or treatment kit that enables diagnosis and treatment ofpatients in need of testosterone therapy. The diagnostic or treatmentkit may comprise one or more testosterone undecanoate compositions ororal dosage forms with one or more other components, including, but notlimited to 1) instructions to enable those ordinarily skilled in the artto prepare a dosage form for immediate dispensing to the subject in needof; 2) one or more containers filled with one or more of the ingredientsof the oral pharmaceutical dosage forms of the invention. Suitablecontainers include, for example, a bottle, a box, a blister card, a foilpacket, or a combination thereof; 3) a tamper proof container orpackaging; 4) other pharmaceutical dosage forms including other activeagents including estrogens, progesterones, PDE-5 inhibitors andglucocorticosteroids; 5) Notice or printed instructions: in a formprescribed by a governmental agency regulating the manufacture, use, orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of the manufacture, use, or sale for humanadministration to treat a condition that could be treated by oraltestosterone therapy; 6) A “planner” for monitoring and trackingadministration of the oral dosage forms; 7) Containers for storing andtransporting the components of the kit. 8) total testosterone or freetestosterone testing kits 9) Sex Hormone binding globulin, SHBG, testingkits 10) Body mass index testing materials to identify high riskpatients; 11) tests for identifying patients with hypogonadism 12) teststo assess testicular function or impotency 13) test for bone mineraldensity/osteoporosis 14) test for hair density 15) test for muscle massand strength 16) test for determining erectile dysfunction 17) test fordecreased libido 18) test for fatigue, depression, mood disorders orirritability 19) test for infertility 20) test for prostate condition21) test for determining hypoactive sexual desire disorder 22) test fordetermining mood disorder. 23) test for determining cardiovasculareffects 24) test for determining cancers such as breast, uterine, etc.

The oral dosage compositions and oral dosage capsules disclosed hereincan be co-administered with other active agents in order to treat atarget condition. For example, phosphodiesterase type 5 (PDE-5)inhibitors, such as sildenafil citrate, tadalafil, vardenafil avanafil,lodenafil, mirodenafil, udenafil, and the like, are used to block thedegradative action of phosphodiesterase type 5 enzyme on cyclic GMP inthe smooth muscle cells lining the blood vessels supplying the corpuscavernosum of the penis and are frequently used to treat erectiledysfunction. Such compounds could be co-administered with thecompositions and oral dosage forms of the present invention in order toprovide improved clinical outcomes through synergistic pharmacologicalaction as measured by improved (sooner, better and longer lasting)erection, potency, libido, mood, body mass, etc. in males relative toadministration of the testosterone or the co-administered PDE-5 alone.The testosterone undecanoate compositions and oral dosage capsules canalso be co-administered with one or more other active agents such asaromatase inhibitors (for example letrozole, anastrozole, exemestane,fadrozole, vorozole, formestane etc.), dopamine agonists (for exampleapomorphine, bromocriptine, cabergoline, pergolide, ropinirole,rotigotine, pramipexole, fenoldopam etc.), prostaglandins (for examplealprostadil), alpha blockers (for example yohimbine, phentolamine),vasodilators (for example minoxidil) and the like, for improved clinicaloutcomes through synergistic pharmacological action as measured byimprovements in one or more of the secondary sexual characteristics inmales such as sexual activity, potency, libido, erection etc., mood,body mass and the like, relative to administration of either thetestosterone or the co-administered active agent alone.

EXAMPLES

The following examples are provided to promote a more clearunderstanding of certain embodiments of the present invention, and arein no way meant as a limitation thereon. Unless otherwisespecified/mentioned, all the compositions provided in the examples arewith respect to % w/w of the final composition. Note that, except in theformulations of Examples 1, 6, 9, 16 and 21 the testosterone undecanoateof all other example formulations can be in either treated (milled,micronized, or nanosized) or untreated form. The testosteroneundecanoate in formulations 1, 6, 9, 16 and 21 are untreated for sizereduction (unmilled, non-micronized, or non-nanosized), and had averageparticle size greater than 50 micrometer.

Examples 1-5 Testosterone Undecanoate Compositions

Testosterone undecanoate formulations of Examples 1 through 5 wereprepared by using the respective components shown in Table I. Example 1is just crystalline untreated (for example, unmilled or non-micronized,having mean particle size more than 50 micrometer). Testosteroneundecanoate filled into a hard gelatin capsule, and Examples 2-5 areprepared as follows: The required quantities of each of the componentsof the respective formulation, except testosterone undecanoate, aretaken in a clean stainless steel container and mixed at about 50° C. to70° C. using a stirrer. A molten clear-to-hazy mixture is obtained. Therequired amount of the testosterone undecanoate is added to theclear-to-hazy mixture and stirred to form a homogenous liquid mixture. Apredetermined weight of the resulting liquid mixture is disposed intoappropriate size capsules according to the testosterone undecanoate doserequired. The capsules were allowed to solidify at room temperature andthen banded, and packaged in HDPE bottles and sealed with a tightlyclosing lid.

Each of the formulations was tested for release of the testosteroneundecanoate using a USP Type II apparatus in 1000 mL of 8 wt % TritonX-100 in water at 37° C. and 100 rpm. The percent of the testosteroneundecanoate released from each formulation was analyzed using HPLC. Theresults of the drug release testing are also shown in Table I. It shouldbe noted that the Example 1 (having TU without a carrier) and Example-2(lipid-based liquid formulation wherein entire TU amount in the dosageunit is solubilized) can be used for comparison purposes to helpillustrate the advantages of the solid compositions and dosage forms ofthe current invention.

TABLE I Composition in % w/w. Ingredients Example 1 Example 2 Example 3Example 4 Example 5 Testosterone Undecanoate 100 12 15 11 18Triglyceride: — 53 — 48 — Ex: Castor Oil NF Lipophilic additive: — 35 —32 — Ex: Lauroglycol FCC Lipophilic additive: — — 63 — 75 GlycerylMonolinoleate, NF Hydrophilic additive: — — 16 — — Polyoxyl 40Hydrogenated Castor Oil, NF Hydrophilic additive: — — 6 9 7 PEG 8000 USP% release in 30 mins 12 100 85 67 62 % release in 120 mins 30 100 101100 100

Testosterone undecanoate formulations of Examples 6 through 9 can beprepared by using the components shown in Table II. Each of theformulations was tested for release of the testosterone undecanoateusing a USP Type II apparatus in 1000 mL of 8 wt % Triton X-100 in waterat 37° C. and 100 rpm.

TABLE II Composition in % w/w. Example Example Example ExampleIngredients 6 7 8 9 Testosterone Undecanoate 90-99 70 (particle >50micrometer) Testosterone Undecanoate — 90 -99 — — micronized ornanosized Testosterone Undecanoate — — 90-99 — (milled) Lactose  1-10 1-10  1-10 30 Organic granulating solvent — — — q.s (example, alcohol)*% release in 30 mins <30 <85 <85 <85 % release in 120 mins <35 >45 >35<35 *removed during drying process.

It should be noted that the compositions of Examples 6 to 9 can beformulated to enable tablet dosage form with the inclusion ofappropriate tabletting aids such as binder, disintegrant, lubricantsetc.

Unlike Example 1 and 6, the calculated drug release profile of Examples7, 8 and 9 shown in Table II, illustrate the advantages of the carrierfor testosterone undecanoate of varied particle size or through organicsolvent granulation.

Example 10 Testosterone Undecanoate Coated Tablets

Testosterone undecanoate tablets of Example 6 through 9 can be furthercoated with a coating solution having typical composition set forth inTable III, using the conventional tablet coating procedures known in theart to a weight gain of about 3.0%.

TABLE III Ingredients Composition in % w/w Hypromellose (Methocel E 5)8.0 Polyethylene glycol, NF 8000 0.6 Isopropyl alcohol, USP 54.8 Water36.6

Examples 11-15 Testosterone Undecanoate Composition

Testosterone undecanoate formulations of Examples 11-15 were prepared byusing the components set forth in Table IV and the method similar tothat described for Examples 2-5. Each of the formulations was tested forrelease of the testosterone undecanoate using a USP Type II apparatus in1000 mL of 8 wt % Triton X-100 in water at 37° C. and 100 rpm. Thepercent of the testosterone undecanoate released from each formulationwas analyzed using HPLC. The release profiles are also shown in TableIV.

TABLE IV Composition % w/w Example Example Example Example ExampleIngredients 11 12 13 14 15 Testosterone Undecanoate 14 14 15 22 25 Oleicacid 75 — — — — Lipophilic additive: — 68 63 — — Glyceryl Monolinoleate,NF Hydrophilic additive: — 7 11 — — Polyoxyl 40 Hydrogenated Castor Oil,NF Polyoxyl 35 Castor Oil, NF — — — — 21 (Cremophor ® EL) GlycerylPalmitostearate — — 5 — — (Glyceryl distearate GDS, Precirol ATO 5)Tocopherol Polyethylene Glycol — — — 22 — Succinate, NF Vitamin E, USP(d,l-α-tocopherol) — — — 34 48 Hydrophilic additive: Polyethylene 11 116 4 6 Glycol 8000, USP Hypromellose (100,000 cPs) — — — 18 — % releasein 30 mins 69 61 34 11 32 % release in 120 mins 100 100 88 48 99

Example 16 Testosterone Undecanoate Tablets

Testosterone undecanoate containing granules for tableting having thecomponents set forth in Table V can be prepared by wet granulationmethods. Accordingly, testosterone undecanoate, microcrystallinecellulose and croscarmellose sodium are passed through an ASTM mesh #40mesh sieve and mixed in a low shear granulator to form a uniform blend.A binder solution of Starch 1500 in deionized water can be used togranulate the dry powder blend to a typical granulation end-point. Thewet granulate dried using a tray dryer or fluid air dryer can be passedthrough a sized/screened, lubricated with Aerosil 200 and magnesiumstearate, and compressed into tablets.

TABLE V Ingredients Composition in % w/w Testosterone Undecanoate 28Microcrystalline Cellulose 52.5 (Avicel PH 102) Croscarmellose sodium 10Pregelatineized starch 8 (Starch1500) Colloidal silicon dioxide 0.5(Aerosil 200) Magnesium stearate 1The tablets of Example 16 exhibit about 30% testosterone undecanoaterelease in the first 120 minutes when tested using a USP Type IIapparatus in 1000 mL of 8 wt % Triton X-100 in water at 37° C. and 100rpm.

Examples 17-22 Testosterone Undecanoate Compositions

Testosterone undecanoate formulations of Table VI are free of lipidsubstances. Examples 17, 18 and 19 were prepared by using the componentsset forth in Table VI and according to the following method: TheTestosterone Undecanoate was dissolved in ethanol along with thecorrespondingly indicated hydrophilic additives. The clear solution soobtained was then slowly poured on microcrystalline cellulose underlow-shear mixing. The granules were dried under a gentle current of airat room temperature. The dried granules were passed through ASTM #40mesh. A predetermined weight of the resulting granules was filled intoappropriate size capsules according to the testosterone undecanoate doserequired.

Testosterone undecanoate formulations of Examples 20, 21 and 22 can beprepared by using the components set forth in Table VI and according tothe following method: The required quantities of the respective inactivecomponent and the testosterone undecanoate, were taken in a cleanstainless steel container and mixed gently at about 50° C. to 70° C.using a stirrer, to get a clear-to-hazy liquid mixture. A predeterminedweight of the resulting liquid mixture is disposed into hard gelatincapsule and allowed to solidify at room temperature.

The dosage forms of each Example 17-22 were tested for release of thetestosterone undecanoate using a USP Type II apparatus in 1000 mL of 8wt % Triton X-100 in water at 37° C. and 100 rpm. The percent of thetestosterone undecanoate released from each formulation was analyzedusing HPLC. The results of the release testing are also shown in TableVI. It should be noted that the compositions of Examples 17-22 can beformulated to enable tablet dosage form with the inclusion ofappropriate tabletting aids such as diluents, binder, disintegrant,lubricants etc.

TABLE VI Composition in % w/w Example Example Example Example ExampleExample Ingredients 17 18 19 20 21 22 Testosterone Undecanoate 45 40 4091 34 60 Hydrophilic additive: — — — 7 30 40 (ex. PEG 8000 USP)Hydrophilic additive: 10 9 9 — — — Sodium Lauryl sulfateMicrocrystalline 45 40 39 — — — Cellulose*, Hydrophilic additive: 0 1111 — — — (ex. Pluronic F 68) Hydrophilic additive: 0 0 1 2 36 — (ex.Polyvinylpyrrolidone (Povidone K 30)) % release in 30 mins 19 23 24 1917 18 % release in 120 mins 52 56 59 48 60 59 *Magnesiumalumnometasilicate (Neuslin ®), lactose and other similar substances canbe used

The in vitro testosterone undecanoate release profiles of Examples 17 to22 could be seen to be superior over the release profile of the Example16.

Examples 23-27 Testosterone Undecanoate Compositions

Testosterone undecanoate formulations of Examples 23-27 were prepared byusing the components set forth in Table VII. Each of the formulationswas prepared by melting the testosterone undecanoate together with thecorresponding inactive component in a stainless steel container at about50° C. to 70° C. with gentle stirring to get a clear-to hazy liquidmixture. A predetermined weight of the resulting liquid mixture isdisposed into hard gelatin capsule and allowed to solidify at roomtemperature. It should be noted that the liquid mixture can also beallowed to solidify to room temperature to get solid aggregates whichmay be sized through a ASTM mesh #30 to get granular particulates, whichcan be further filled in hard gelatin capsules.

Each of the formulations was tested for release of the testosteroneundecanoate using a USP Type II apparatus in 1000 mL of 8 wt % TritonX-100 in water at 37° C. and 100 rpm. The percent of the testosteroneundecanoate released from each formulation was analyzed using HPLC. Theresults of the release testing are also shown in Table VII.

TABLE VII Composition in % w/w Example Example Example Example ExampleIngredients 23 24 25 26 27 Testosterone 91 50 25 20 85 UndecanoateHydrophilic additive:  9 50 75 — — (e.g. Povidone K 17) Lipophilicadditive: — — — 80 15 (e.g. Glycerol esters of C₁₂-C₁₈ fatty acids) %release in 30 mins 12 20 15 35 16 % release in 120 mins 32 50 65 48 43

Example 28 Testosterone Undecanoate Spray Dried Multiparticulates

Testosterone undecanoate multiparticulates can be prepared as follows:15 g of a milled testosterone undecanoate and lactose, mixture (95:5w/w), are passed through ASTM mesh #60 sieve and added under mixing toabout 250 mL solution of, 8% w/v povidone K17 in water The resultingsuspension can be spray dried using a conventional spray dryingequipment with settings, for example, at heat inlet temperature of about60-75° C. and an outlet temperature of about 30-38° C., aspirator set at90-100%, the pump set at about 8-12 mL/min, and the flow rate set atabout 500-600 L/hr. The final solid multiparticulate testosteroneundecanoate composition can have a compositional makeup of about 53 wt %testosterone undecanoate, about 2.8 wt % lactose and about 44.2 wt %povidone K17.

Example 29 Testosterone Undecanoate Cyclodextrin Complexes

Testosterone undecanoate cyclodextrin complexes can be prepared byco-precipitation methods using various molar ratios of 1:1, 2:1, 3:1,and 1:2 of the testosterone undecanoate to beta-cyclodextrin,respectively. A significantly increased release rate of testosteroneundecanoate can be achieved with the cyclodextrins complexes in an invitro release testing in about 1000 mL of a 8% w/w Triton X-100 solutionat 37° C. in a USP-2 apparatus set at 100 rpm, when compared to the freeform of the drug. Granulates of the cyclodextrin/testosteroneundecanoate complex can be made using the standard granulation orpelleting techniques using additional conventional pharmaceuticalprocessing aids known in the art.

Example 30-34 Testosterone Undecanoate Compositions

A mixture of testosterone undecanoate and the corresponding formulationcomponents can be melted together to get thermosetting fill to bedisposed into capsule. Alternatively, the mixture can be fed into amelt-extruder apparatus for example, a single-screw extruder (Killion,Model KLB 100) equipped with about 1 inch diameter screw and about 6inch flex lip die, and the die opening adjusted to about 0.005 inchesand the screw speed was set at about 50 rpm. The residence time of thematerials within the extruder can be set for about 2 to 8 minutes. Theextruded strands can be cooled to room temperature by passing over achilled roll. The strands can then be sized through an ASTM mesh #40 andthe powder disposed into capsules. The exemplary formulations formelt-extrusion are indicated in Table VIII. These dosage forms canrelease 35% or more testosterone undecanoate in about first 120 minutesand about 85% or less in the first 30 minutes.

It should be noted that the testosterone undecanoate compositions ofTable VIII can be further formulated to include one or more of othersubstances such as lactose, starches, hydroxypropyl methyl cellulose,methacrylate etc., at varying concentrations from about 12% to about 88%by weight of the total composition either prior to melt-extrusion orafter sizing the melt-extruded composition, in order to prepare solidmulti-particulates for tablets.

TABLE VIII Composition in % w/w Example Example Example Example ExampleIngredients 30 31 32 33 34 Testosterone 70 40 50 80 60 UndecanoatePolyethylene glycol 10 — 20 15 20 8000 USP (Glyceryl distearate 10 40 20— — GDS, Precirol ATO 5) Stearic acid 10 20 10 — Cholesterol — — —  5 20

Example 35 Testosterone Undecanoate Compositions Produced by Co-Milling

A testosterone undecanoate containing composition can be prepared byco-milling (co-grinding) 80 g solid testosterone undecanoate along with15 g PVP K 17 and 5 g of sodium lauryl sulphate for a period from about12 hours to about 24 hours using a ceramic ball-mill maintained at about20±5° C. The co-milled composition can provide a superior in vitro drugrelease profile which could be at least 20% more when compared to the invitro release profile of Example 1 when tested using a USP Type IIapparatus in 1000 mL of 8 wt % Triton X-100 in water at 37° C. and 100rpm.

Example 36 Testosterone Undecanoate Loaded Pellets

Testosterone undecanoate coated pellets were prepared using theingredients set forth in Table IX. A spraying solution of the coatingmaterials can be prepared by dissolving 25 g of testosteroneundecanoate, 6 g of Pluronic F 68 and 5 g of PVP K 30 in about 250 mL ofdehydrated alcohol. The spray solution can be intermittently sprayed onto a rolling bed of 64 g commercially available microcrystallinecellulose spheres (for example, having a mean particle size in the rangeof about 250 μm to about 600 μm) taken in a convention coating pan.After all the spray solution is loaded on the spheres, it can be driedunder gentle current of air for at least 1 hour to remove the solvent.Thus, by adjusting the pan speed, spray rate and the inlet air flow andtemperature, the testosterone undecanoate loaded pellets or beads can beobtained which can be disposed into a capsule. Auxiliary pharmaceuticalprocess aids such as talc, starch etc. may be dusted during the sprayingprocess to avoid agglomeration of the pellets.

It should be noted that appropriate similar or equivalent equipmentknown in the art may be used for the purpose. Also, by varying thequantity of spray solution sprayed on the spheres or by varying theconcentration of testosterone undecanoate in the spray solution, pelletsof different drug loading can be achieved.

TABLE IX Ingredients Composition in % w/w Testosterone Undecanoate 25Pluronic F 68 6 Polyvinylpyrrolidone K 30 5 Dehydrated Alcohol 250 mLmicrocrystalline cellulose spheres (Celsphere) 64

Example 37 Testosterone Undecanoate Composition with HydrophilicAdditive

Enhancement of the release rate of testosterone undecanoate can beachieved by eutectic or non-eutectic mixtures with a hydrophilicadditive such as polyethylene glycol (PEG), particularly PEG havingmolecular weights of about 1000 or more. For example, about 1 g oftestosterone undecanoate can be combined with 0.3 g of PEG (molecularweight 8000) and 0.5 g of Poloxamer (Pluronic F68). The mixture can bemelted at about 60° C.-70° C. under stirring and then subsequentlysolidified to room temperature. The resulting solid can be sized throughan ASTM mesh #30 and filled into capsule or pressed into a tablet. Itshould be noted that pharmaceutical aids such as diluents, disintegratesand/or lubricants can be optionally used to get the tablets or capsules.

Example 38 Testosterone Undecanoate Compositions with LipophilicAdditive

Enhancement of the release rate of testosterone undecanoate can beachieved by eutectic or non-eutectic mixtures with a lipophilic additivesuch as hydrogenated castor oil, glyceryl palmitostearate, glyceryldistearate, stearic acid etc. For example, about 10 g of testosteroneundecanoate can be combined with 0.5 g of glyceryl palmitostearate(Precirol® ATO 5) and 1 g of stearic acid. The mixture can be melted atabout 60° C.-70° C. under stirring and allowed to solidify at roomtemperature. The resulting solid can be sized through an ASTM mesh #30and filled into capsule or pressed into a tablet. It should be notedthat pharmaceutical aids such as diluents, disintegrates and/orlubricants can be optionally used to get the tablets or capsules.

Numerous modifications and alternative arrangements may be devised bythose skilled in the art without departing from the spirit and scope ofthe present invention and the appended claims are intended to cover suchmodifications and arrangements. Thus, while the present invention hasbeen described above with particularity and detail in connection withwhat is presently deemed to be the most practical and preferredembodiments of the invention, it will be apparent to those of ordinaryskill in the art that variations including, but not limited to,variations in size, materials, shape, form, function and manner ofoperation, assembly and use may be made without departing from theprinciples and concepts set forth herein.

1. A solid oral dosage form, comprising: a therapeutically effectiveamount of testosterone undecanoate, and a pharmaceutically acceptablecarrier, wherein when tested using a USP Type II apparatus in 1000 mL of8 wt % Triton X-100 in water at 37° C. and 100 rpm, the oral dosage formreleases at least 20% more testosterone undecanoate after the first 120minutes than an equivalent dose testosterone undecanoate containing oraldosage form without the pharmaceutically acceptable carrier.
 2. Thesolid oral dosage form of claim 1, wherein the testosterone undecanoateis present as a solid particulate.
 3. The solid oral dosage form ofclaim 1, wherein the oral dosage form does not form an oil-in-wateremulsion upon contact with water.
 4. The solid oral dosage form of claim1, wherein the pharmaceutically acceptable carrier includes a compoundselected from the group consisting of hydrophilic additives, lipophilicadditives, or combinations thereof.
 5. The dosage form of claim 1,wherein the pharmaceutical carrier is not a lipid substance with chainlength greater than C₁₂.
 6. The solid oral dosage form of claim 1,wherein the pharmaceutically acceptable carrier includes a compoundselected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidones, polyethylene glycols having molecular weight from about100 to about 20,000; cyclodextrins; maltodextrin; hydroxypropyl methylcellulose; carbomers; gelatin; poloxamers; ethyl alcohol; benzylalcohol; benzyl benzoate, and combinations thereof.
 7. A The solid oraldosage form of claim 1, wherein the pharmaceutically acceptable carrierincludes a compound selected from the group consisting of ethylcellulose, cellulose acetate phthalates, glyceryl distearate, acrylicacid and methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer, poly(methyl methacrylate),poly(methacrylic acid) (anhydride), methyl methacrylate,polymethacrylate, stearic acid, poly(methyl methacrylate) copolymer,polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acidanhydride), and glycidyl methacrylate copolymers.
 8. The solid oraldosage form of claim 4, wherein the composition includes a hydrophilicadditive that is not a hydrophilic surfactant.
 9. The solid oral dosageform of claim 4, wherein the composition includes a lipophilic additivethat is not a lipophilic surfactant.
 10. The solid oral dosage form ofclaim 4, wherein the composition is free of triglycerides, animal andvegetable oils.
 11. The solid oral dosage form of claim 1, wherein thetestosterone undecanoate is present in an amount of about 0.5 mg toabout 750 mg.
 12. The solid oral dosage form of claim 1, wherein theoral dosage form is formulated for administration to a human female andthe testosterone undecanoate is present in an amount of about 0.5 mg toabout 200 mg.
 13. The solid oral dosage form of claim 1, wherein theoral dosage form is formulated for administration to a human male andthe testosterone undecanoate is present in an amount of about 50 mg toabout 750 mg.
 14. The solid oral dosage form of claim 1, wherein theoral dosage form releases about 85 wt % or less of the testosteroneundecanoate in the first 30 minutes.
 15. The solid oral dosage form ofclaim 1, wherein the oral dosage form releases about 70% or less of thetestosterone undecanoate in the first 30 minutes.
 16. The solid oraldosage form of claim 1, wherein the oral dosage form releases at least35 wt % of the testosterone undecanoate in the first 120 minutes. 17.The solid oral dosage form of claim 1, wherein the oral dosage formreleases at least 45 wt % of the testosterone undecanoate in the first120 minutes.
 18. The solid oral dosage form of claim 1, wherein, whenadministered to a human male, the oral dosage provides a dose to plasmatotal testosterone C_(avg) ratio of 4.5×10⁴ dL to 4×10⁶ dL.
 19. Thesolid oral dosage form of claim 1, wherein, when administered to a humanfemale, the oral dosage provides a dose to plasma total testosteroneC_(avg) ratio of 5×10³ dL to 2×10⁷ dL.
 20. The oral dosage capsule ofclaim 1 wherein the oral dosage form upon single administration to ahuman subject, provides a ratio of serum testosterone undecanoateC_(avg) to serum total testosterone C_(avg) of about 3:1 to about 100:1.21. The solid oral dosage form of claim 1, wherein the oral dosage formhas a testosterone undecanoate to pharmaceutically acceptable carrierratio of about 8:1 (w/w) to about 1:8 (w/w).
 22. The solid oral dosageform of claim 1, wherein the oral dosage form has a testosteroneundecanoate to pharmaceutically acceptable carrier ratio of about 4:1(w/w) to about 1:4 (w/w).
 23. The solid oral dosage form of claim 1,wherein the oral dosage form is a tablet or a capsule.
 24. The solidoral dosage form of claim 1, wherein the oral dosage form is amultiparticulate oral dosage form.
 25. The solid oral dosage form ofclaim 1, wherein the testosterone undecanoate is present in an amorphousand/or crystalline form having a mean particle diameter of about 30 μmor less.
 26. The solid oral dosage form of claim 1, wherein, when afteradministration to a human male, the oral dosage form provides a plasmatotal testosterone C_(avg) of about 300 ng/dL to about 1100 ng/dL. 27.The solid oral dosage form of claim 1, wherein, when afteradministration to a human male, the oral dosage form provides a plasmatotal testosterone C_(avg) of about 350 ng/dL to about 800 ng/dL. 28.The solid oral dosage form of claim 1, wherein, when afteradministration to a human male, the oral dosage form provides a plasmatotal testosterone C_(avg) of about 400 ng/dL to about 600 ng/dL
 29. Thesolid oral dosage form of claim 1, wherein, when after administrationsto a human male, the oral dosage form provides a testosteroneundecanoate C_(avg) of about 1.5 ng/mL to about 1 μg/mL.
 30. The solidoral dosage form of claim 1, wherein, when after administrations to ahuman male, the oral dosage form provides a testosterone undecanoateC_(avg) of about 10 ng/mL to about 850 ng/mL.
 31. The solid oral dosageform of claim 1, wherein when administered to a human female, the oraldosage form provides a plasma total testosterone C_(avg) of about 1ng/dL to about 100 ng/dL.
 32. The solid oral dosage form of claim 1,wherein, when administered to a human female, the oral dosage formprovides a plasma total testosterone C_(avg) of about 20 ng/dL to about80 ng/dL.
 33. The solid oral dosage form of claim 1, wherein, whenadministered to a human female, the oral dosage form provides a plasmatotal testosterone C_(avg) of about 30 ng/dL to about 70 ng/dL.
 34. Amethod of treating a subject in need of testosterone therapy,comprising: administering a solid oral dosage form of claim 1 to thesubject.
 35. The method of claim 34 wherein the administration is doneonce every 24 hours.
 36. The method of claim 34 wherein theadministration is done once every 12 hours.
 37. The method of claim 34wherein the subject is a male and the need for testosterone therapy isassociated with a condition selected from the group consisting ofhypogonadism; erectile dysfunction; Klienfelter Syndrome; reducedlibido; low muscle mass and low bone density; metabolic syndrome, andcombinations thereof.
 38. The method of claim 34 wherein the subject isa human male and the solid oral dosage form provides a daily dose oftestosterone undecanoate of about 50 mg to about 1500 mg per day. 39.The method of claim 34 wherein the subject is a female and the need fortestosterone therapy is associated with a condition selected from thegroup consisting of hypoactive sexual desire disorder, arousal disorder,dyspareunia, anorgasmia, and combinations thereof.
 40. The method ofclaim 34 wherein the subject is a human female and the solid oral dosageform provides a daily dose of testosterone undecanoate of about 0.5 mgto about 200 mg per day.